Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in female SAMP8, a model of accelerated senescence

Abstract

Senescence accelerated mice P8 (SAMP8) is a phenotypic model of age, characterized by deficits in memory and altered behaviour. Here, we determined the effect of age in SAMP8, and compared with the resistant strain, SAMR1, in behaviour and learning parameters linking these disturbances with oxidative stress environment. We found impairment in emotional behaviour with regard to fear and anxiety in young SAMP8 vs. age-mated SAMR1. Differences were attenuated with age. In contrast, learning capabilities are worse in SAMP8, both in young and aged animals, with regard to SAMR1. These waves in behaviour and cognition were correlated with an excess of oxidative stress (OS) in SAMP8 at younger ages that diminished with age. In this manner, we found changes in the hippocampal expression of ALDH2, IL-6, HMOX1, COX2, CXCL10, iNOS, and MCP-1 with an altered amyloidogenic pathway by increasing the Amyloid beta precursor protein (APP) and BACE1, and reduced ADAM10 expression; in addition, astrogliosis and neuronal markers decreased. Moreover, Superoxide dismutase 1 (SOD1) and Nuclear factor-kappa beta (NF-kβ) expression and protein levels were higher in younger SAMP8 than in SAMR1. In conclusion, the accelerated senescence process present in SAMP8 can be linked with an initial deregulation in redox homeostasis, named neuroinflammaging, by inducing molecular changes that lead to neuroinflammation and the neurodegenerative process. These changes are reflected in the emotional and cognitive behaviour of SAMP8 that differs from that of SAMR1 and that highlighted the importance of earlier oxidative processes in the onset of neurodegeneration.

SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions

“…This suggests the epigenetic landscape change in SAMP8 as a key point for achieving a protective action, at least at the brain level. Therefore, novel therapeutics can be developed for neurodegenerative diseases, including AD, by focusing on epigenetic targets using the SAMP8 strain …”

“…Therefore, novel therapeutics can be developed for neurodegenerative diseases, including AD, by focusing on epigenetic targets using the SAMP8 strain. [63][64][65] According to the traditional understanding of CSF physiology, the majority of CSF is produced by the choroid plexus and circulates through the ventricles, the cisterns and the subarachnoid space to be absorbed into the blood by the arachnoid villi. However, recent novel insights indicate that CSF dynamics and pathophysiology may be much more complex than previously understood.…”

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

“…The defective learning and memory capacities of SAMP8 mice have been shown in different experimental tasks, including hippocampus-based spatial learning and memory and object recognition tasks (Dobarro et al, 2013;López-Ramos et al, 2012;Miyamoto et al, 1986;Wang et al, 2009;Yanai and Endo, 2016). Pathological changes are mainly present in the hippocampal area and include the following: (i) reduced synaptic plasticity with impaired long-term potentiation (LTP) (López-Ramos et al, 2012;Taniguchi et al, 2015) and lower activation of plasticity pathways (Li et al, 2009;Lin et al, 2014);(ii) increased levels of hyperphosphorylated tau (p-tau) with tau-related enzyme disorder (Álvarez-García et al, 2006;Canudas et al, 2005;Dobarro et al, 2013); (iii) higher accumulation of amyloid β peptides (A ) (Dobarro et al, 2013;Kumar et al, 2009;Zhang et al, 2011) which would be caused by an abnormally elevated synthesis of Aβ protein precursor (AβPP) (Griñán-Ferré et al, 2016;Morley et al, 2000) in addition to disturbances in the blood-brain barrier (Banks et al, 2011); (iv) oxidative stress (Álvarez-García et al, 2006;Butterfield et al, 1997;Morley et al, 2012); and (v) increased inflammation (Álvarez-López et al, 2014;Griñán-Ferré et al, 2016;Tha et al, 2000).…”

Longitudinal Performance of Senescence Accelerated Mouse Prone-Strain 8 (SAMP8) Mice in an Olfactory-Visual Water Maze Challenge

“…An established and widely used line of mice that feature accelerated aging are the Senescence Accelerated Mouse Prone (SAMP) strains (Takeda, 1999). Three decades of research support the contention that of these, SAMP strain-8 (SAMP8) is an appropriate model for considering human-aging, because pathological traits are age-dependent and occur as a consequence of epigenetic changes with age and heightened glucocorticoid exposure that synergistically promote oxidative stress (Flood and Morley, 1998; Hosokawa, 2002; Chiba et al, 2009; Griñan-Ferré et al, 2016a; Grinan-Ferre et al, 2016b; Puigoriol-Illamola et al, 2018). SAMP8 mice show normal development, but thereafter, have early loss of reproductive function and tend to demonstrate early manifestation of neurodegenerative features including neuronal cell loss and a reduction in neurotransmitter release (Sureda et al, 2006; Pallàs, 2012; Bernstein et al, 2014).…”